Cigarette smoking is the largest single preventable cause of premature death and disability. Counseling habitual cigarette smokers on smoking cessation techniques is a health-promoting intervention used frequently by clinicians in their practice. However, quitting smoking is difficult due to the tobacco withdrawal syndrome and dysphoric states reported to accompany cessation. These dysphoric states may be partially explained by a reduction in endogenous opioid peptides which are known to influence mood and analgesia. Endogenous opioid peptides have also been implicated in exercise. The goals of this FIRST Award are to examine the relationships of nicotine, endogenous opioid peptides, antinociception, dysphoric states and exercise and their influence on smoking behavior through a logical sequence of human and animal studies. The proposed inpatient human study is a six-day repeated measures experimental design. Male and female adult habitual smokers will be admitted to the General Clinical Research Center and will be randomly assigned to an experimental or control group. Experimental subjects will smoke ad libitum and receive naltrexone, an oral opioid antagonist, during the course of the protocol. Control group subjects will also smoke ad libitum and will receive a placebo. Dependent measures include: 1) number of cigarettes smoked/day; 2) expired air carbon monoxide level; 3) plasma nicotine level; and 4) subjective measures of withdrawal symptoms and mood. Several animal experiments are included in this FIRST Award proposal. These experiments will examine the antinociceptive effect of nicotine and allow direct measurement of opioid peptide levels as well as opioid receptor binding in an animal model of nicotine dependence. The first animal study will examine the effect of chronic nicotine administration on: 1) tail-flick latency; 2) met-enkephalin, leu-enkephalin, dynorphin and beta-endorphin; and 3) mu, delta, and kappa opioid receptor binding. The second animal study will examine the effect of nicotine withdrawal on the same dependent variables. Finally, the third set of animal experiments are designed to examine the effect of exercise on tail-flick latency and endogenous opioid peptide levels in naive and nicotine-withdrawn animals. Understanding the mechanisms responsible for tobacco withdrawal symptoms and dysphoric mood states is critical to developing therapeutic interventions aimed at improving successful smoking cessation. Determining the effect of exercise on endogenous opioid peptides will provide the scientific basis for future investigation of interventions aimed at reducing relapse to smoking.